The present invention is generally directed to processes for the synthesis of morphinans, more specifically, nordihydrothebainone and its analogs.
Nordihydrothebainone and its derivatives are important synthetic intermediates to many morphinan compounds including burprenorphine, codeine, etorphine, hydrocodone, hydromorphone, morphine, nalbuphine, nalmefene, naloxone, naltrexone, oxycodone, and oxymorphone. Generally, these compounds are analgesics, which are used extensively for pain relief in the field of medicine due to their action as opiate receptor agonists. However, nalmefene, naloxone and naltrexone are opiate receptor antagonists; and are used for reversal of narcotic/respiratory depression due to opiate receptor agonists.
Various processes for the synthesis of nordihydrothebainone and its analogs are known. Generally, a Grewe cyclization reaction is used to obtain nordihydrothebainone. In U.S. Pat. No. 4,368,326, Rice discloses a process of preparing a nordihydrothebainone (e.g., 1-bromo-N-formylnordihydrothebainone) from a β,γ-hexahydroisoquinolinone (e.g., 1-(2′-bromo-4′-methoxy-5′-hydroxybenzyl)-2-formyl-1,3,4,5,7,8-hexahydroisoquinolin-6-one) by Grewe cyclization catalyzed using a super acid catalyst alone or with a combination of an ammonium fluoride complex and trifluoromethanesulfonic acid.
Contaminants in the starting β,γ-hexahydroisoquinolinone used in the Grewe cyclization cause reproducibility problems and low yields of the desired cyclized product. One known method for increasing the reproducibility and yield of the Grewe cyclization step is to purify the starting β,γ-hexahydroisoquinolinone by crystallization. However, crystallization of the β,γ-hexahydroisoquinolinone is difficult since it typically consists of a mixture of rotational isomers. In addition, α,β-hexahydroisoquinolinones are isomeric by-products of the Grewe cyclization of β,γ-hexahydroisoquinolinones. Under conventional conditions, the α,β-hexahydroisoquinolinone does not undergo the Grewe cyclization reaction to an appreciable extent to form the desired nordihydrothebainone product. Accordingly, known Grewe cyclization conditions often produce low yields of the nordihydrothebainone product due to a significant amount of the β,γ-hexahydroisoquinolinone starting material being converted into α,β-hexahydroisoquinolinones.
The presence of water is one factor that affects the reproducibility and yield of the Grewe cyclization reaction. Water in the reaction mixture may reduce selectivity by contributing to the conversion of the β,γ-hexahydroisoquinolinone starting material into undesirable α,β-hexahydroisoquinolinones. Water may be introduced into the Grewe cyclization reaction medium from the starting β,γ-hexahydroisoquinolinone and the cyclizing acid reagents used. Generally, commercially available acids used to catalyze the Grewe cyclization have a measurable amount of water present because of their hygroscopic nature. Other contaminants known to affect the yield of the Grewe cyclization reaction are alcohols and organic acids.
The undesirable α,β-hexahydroisoquinolinone isomer by-products produced during the Grewe cyclization reaction can be difficult to separate and once separated are typically discarded. This practice results in a significant loss in productivity and efficiency due to the many steps necessary to synthesize the starting β,γ-hexahydroisoquinolinone; for example, starting with 3-methoxyphenethylamine as described by Rice in U.S. Pat. No. 4,368,326. Being able to regenerate the β,γ-hexahydroisoquinolinone starting material would significantly reduce the amount of wasted material, capital equipment, labor, and improve overall yield in the synthesis of nordihydrothebainone products.
Thus, a need persists for processes for the synthesis of nordihydrothebainone and analogs thereof including Grewe cyclization capable of inhibiting by-product formation and increasing yields.